1. Field of the Invention
This invention relates to the enantioselective synthesis of pyrroloindole compounds that are useful as intermediates for the synthesis DNA minor groove binder alkylators.
2. Description of Related Art
Double helical DNA has two longitudinal spiral grooves running along its exterior, much like the stripes on a barbershop pole. The two grooves are not identical: one, called the major groove, is much wider than the other, called the minor groove.
The width of the minor groove is approximately equal to the thickness of a benzene ring. Many biologically active DNA-binding molecules are substantially planar polyaromatic molecules having an arcuate footprint, such shape enabling them to fit snugly in the minor groove. One class of these molecules not only bind to DNA, but also alkylate it and are referred to as DNA minor groove binder-alkylators (“MGBAs”).
An MGBA subclass is represented by the natural products CC-1065, duocarmycin SA, and yatakemycin (Boger and Johnson 1995; Tichenor et al. 2007). (Full citations for the documents cited herein by first author or inventor and year are listed at the end of this specification in the REFERENCES subsection.) They comprise an alkylating subunit and one or more binding subunits, the latter contributing to binding to DNA but being chemically unreactive towards it. In CC-1065 and duocarmycin SA, the alkylating subunit is at one end of the molecule and the binding subunit(s) are at the other end. In yatakemycin, the alkylating subunit is flanked by binding subunits. Consonant with the overall MGBA architecture, the alkylating and binding subunits themselves are polyaromatic and substantially planar. As the alkylating subunit has a cyclopropapyrroloindole (“CPI”) core structure, MGBAs in this subclass are eponymously referred to as CPI compounds.

Upon binding to DNA, the CPI cyclopropyl ring is activated and alkylates DNA at an adenine N3 nitrogen (Hurley et al. 1984). One theory proposed to explain the activation is that binding introduces further conformational strain into the already-strained cyclopropyl ring, increasing its reactivity (Boger 2001; Boger et al. 1997b; Tichenor et al. 1997).

Seco-CPI compounds are variants of CPI compounds in which the cyclopropyl ring has been opened and replaced with a halomethyl group. While seco-CPI compounds themselves do not alkylate DNA, they are readily convertible in vitro or in vivo to CPI compounds and their biological activity is essentially the same as the latter's (Li et al. 2012). Thus, seco-CPI compounds are of interest as synthetically convenient functional equivalents of CPI compounds or as intermediates for their synthesis (Boger et al. 2000).

An advantage of a seco-CPI compound is that it can be prodrugged to control conversion to the CPI form. Attaching a prodrugging group PD to the phenolic hydroxyl group prevents conversion to the CPI form unless PD is cleaved off first. PD can be chosen such that it is cleaved by an agent found at or near the site of intended biological action, such as a tumor, to reduce the risk of systemic toxicity. PD preferably is an enzymatically cleavable group, such as a carbamate, phosphate, glycoside, or glucuronide, which are cleavable by carboxyesterase, phosphatase, glycosidase, or glucuronidase, respectively. See, e.g., Kobayashi et al. 1994; Lajiness et al. 2010; Sufi et al. 2013; Tietze et al. 2001; Zhang et al. 2014.

CPI and seco-CPI compounds are potent cytotoxins, making them attractive candidates as anti-cancer agents. Substantial research efforts have been dedicated to synthesizing and evaluating their analogs for such use. A key challenge in the synthesis of CPI and seco-CPI compounds is the alkylating subunit, with its tricyclic structure and, in the case of CPI compounds, an additional fused cyclopropyl ring. Numerous disclosures relating to CPI and seco-CPI synthesis exist, including Boger et al. 1988, 1993, 1997a, and 2000; Boyle et al. 2010; Choi et al. 2009; Fukuda et al. 1994, 1997a, 1997b, and 1997c; Hiroya et al. 2004; Kinugawa et al. 1998; Kraus et al. 1985; Kuwano et al. 2004; Muratake et al. 1994, 1995, 1998a, 1998b, and 2000; Sakamoto et al. 1993; Tichenor et al. 2006; and Yamada et al. 2003.